The alkaloids obtainable from Vinca rosea represent one of the most productive areas of chemistry for drugs which adversely affect the growth of experimental malignancies in mammals. Initially, only some of the alkaloids, obtainable from the leaves of the plant by extraction and purifiable by chromatography, were found to be active. These active antineoplastic alkaloids obtained directly from the leaves of the vinca plant were all found to have a dimeric indole-dihydroindole structure: ##STR1##
In the above formula, where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, VLB (vincaleucoblastine, vinblastine) is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl, and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl or formyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together with the carbons to which they are attached form an .alpha.-epoxide ring, leurosine and leuroformine, respectively are represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, and R.sup.4 and R.sup.5 are H, deoxy VLB "B" or 4'-deoxyleurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.4 is ethyl and R.sup.3 and R.sup.5 are H, deoxy VLB "A" or 4'-deoxy VLB is represented; where R.sup.1 is H, R.sup.3 and R.sup.5 are OH, R.sup.4 is ethyl and R.sup.2 is CH.sub.3, 4-desacetoxy-3'-hydroxy VLB is represented; where R.sup.1 and R.sup.5 are H, R.sup.3 is OH, R.sup.4 is ethyl and R.sup.2 is methyl, 4-desacetoxy VLB is represented; and where R.sup.1 is acetoxy R.sup.3 and R.sup.5 are OH, R.sup.4 is ethyl and R.sup.2 is methyl, vincadioline is represented.
Literature references to the above alkaloids are as follows: leurosine (U.S. Pat. No. 3,370,057), VLB (U.S. Pat. Nos. 3,097,137, and 4,305,875), leuroformine (Belgian Patent No. 811,110), leurosidine (vinrosidine) and leurocristine (to be referred to hereafter as vincristine) (both in U.S. Pat. No. 3,205,220), vincadioline (U.S. Pat. No. 3,887,565), 4-desacetoxy VLB (U.S. Pat. No. 3,954,773), and 4-desacetoxy-3'-hydroxy VLB (U.S. Pat. No. 3,944,554).
Two of the above alkaloids, VLB and vincristine, are now marketed for the treatment of malignancies, particularly the leukemias and related diseases, in humans. The two marketed alkaloids are customarily administered by the i.v. route. Two others, leurosidine and leuroformine, have been on clinical trial in the U.S. or in Europe.
Chemical modification of the Vinca alkaloids started slowly for several reasons. In the first place, the molecular structures involved are extremely complex, and chemical reactions which modify one specific functional group of the molecule without affecting other groups have been difficult to develop. Secondly, dimeric alkaloids lacking desirable chemotherapeutic properties have been recovered or produced from Vinca rosea extracts, and a determination of their structures has led to the conclusion that these inactive compounds are closely related structurally to, and even isomeric with, one or more of the active alkaloids.
One of the more recent, and more successful, modifications of the basic indole-dihydroindole structure has been the preparation of C-3 carboxamide and carboxhydrazide derivatives. Many of these are highly active anti-tumor agents (see U.S. Pat. 4,166,810, and Conrad et al. J. Med. Chem., 22, 391 (1979). 4-Desacetyl VLB 3-carboxamide (vindesine) is currently being marketed in several European countries as an oncolytic agent. It is said to be effective in treating some vincristine-resistant leukemias.
Most of the chemical modifications of the dimeric indole-dihydroindole alkaloids have involved modifying a functionality already present in the molecule; i.e., ester to amide at C-3, changing C-4 ester group, formyl for methyl at N-1, dehydration at C-4' and adjacent carbons, converting C-3 hydroxy and ester to spiro-oxazolidinedione, changing 3',4'-epoxide to 3'-hydroxy etc. Direct substitution of new chemical groups or atoms into the complex ring structure has been rare; see, for example, preparation by Barnet et al. (U.S. Pat. No. 4,110,330) of a 5'-acetonyl VLB derivative where the acetonyl group (CH.sub.3 --CO--CH.sub.2) replaces one of the C-5' hydrogens.
Aromatic substitution in the vindoline (dihydroindole) moiety is known and the substituent usually enters the ring at C-17, ortho to both the methoxy and dialkylamine groups--see for example Teale et al., Brit. J. Pharm., 4, 169(1977) who also prepared C-9' derivatives. Substitution in the phenyl moiety of the upper indole (catharanthine) portion of the molecule is not known, probably because aromatic substitution is favored at C-17 in the lower portion for the reasons set forth above.
A combination of iodine and periodic acid in acetic acid have been used to iodinate polyalkylbenzenes containing bulky groups--see Bull. Chem. Soc. (Japan), 39, 129 (1956).
It is an object of this invention to provide 12'-iodo substituted dimeric indole-dihydroindoles.